Early and Late Hepatitis B Reactivation After IFN- or DAA-based Therapy of Recurrent Hepatitis C in Anti-HBc-positive Liver Transplant Recipients.

Abstract

hepatitis B virus (HBV) reactivation (HBVr) after inhibition of hepatitis C virus (HCV) in HBsAg-negative/anti–HBc-positive patients is a rare event and, recently, it was described belatedly after therapy with direct-acting antiviral(s) (DAAs) in a liver transplant (LT) recipient.1 We describe 2 cases of LT recipients who developed HBVr after DAA, off-therapy, and after HCV ribonucleic acid (RNA) inhibition with Interferon (IFN), on-therapy. Neither case had risk factors for de novo hepatitis B virus (HBV) infection. CASE 1 A 57-year-old man underwent LT for HCV-related cirrhosis, genotype 1b, in 2011; before surgery, he was anti–HBc-positive and HBV deoxyribonucleic acid (DNA)-negative. The donor was negative for all the HBV markers. After LT, the patient was treated with tacrolimus without evidence of rejection. In 2015, a liver biopsy detected HCV-related cirrhosis evolution and a 24-week cycle of DAA (sofosbuvir/ledipasvir) and ribavirin (RBV) was started obtaining sustained virological response. During the half-yearly monitoring and before DAA treatment HBsAg and HBV DNA were negative. Sixteen months after the end of DAA treatment, in the absence of variations of the immunosuppressive regimen, he developed a hepatitis flare with HBVr (HBsAg positive and HBV DNA 6.9 × 106 IU/mL). Thus, immunosuppression was reduced and Entecavir introduced with a progressive normalization of liver function tests and undetectable HBV-DNA (Figure 1).FIGURE 1: HBV reactivation after DAA (case 1) or IFN (case 2)-based therapy of recurrent hepatitis C in 2 anti–HBc-positive LT recipients.CASE 2 A 58-year-old man underwent LT for HCV-related cirrhosis, genotype 1b in 2010. At that time, he was HBsAg-negative, HBV DNA-negative and anti–HBc-positive. The donor was negative for HBV markers. Three unsuccessful attempts of IFN-based therapy were performed before LT. After LT and during the anti-HCV treatment, the patient was treated with cyclosporine without evidence of rejection. Hepatitis C virus recurrence was diagnosed 3 months after LT, and 1 year later, he was newly treated with IFN and RBV. Hepatitis C virus RNA became negative after 3 months but therapy was stopped 2 months later because of HBVr (HBsAg positive and HBV DNA 2,746 IU/mL). Entecavir was introduced with subsequent HBsAg and HBV DNA negativization, whereas HCV RNA relapsed. In 2014, he was treated with DAA (sofosbuvir) and RBV for 24 weeks achieving sustained virological response (Figure 1). DISCUSSION In many coinfected patients, HCV prevails on HBV. Inhibition of HCV can change this balance inducing HBVr, defined as HBsAg reappearance in anti-HBc positive and/or an increase in HBV replication and hepatitis in HBsAg-positive patients.2 Considering the past experience with IFN, owing to the dual action of the drug on both HCV and HBV replication, HBVr has been observed in only small numbers of patients. In contrast to IFN, DAA do not have any anti-HBV properties, and the risk of reactivation seems higher, particularly in HBsAg-positive patients. Moreover, HBVr can occur during treatment (more often within 4 to 8 weeks) or after the end of therapy.3 To date in the LT setting, only 1 case of HBVr has been described after treatment with DAA in 1 anti–HBc-positive recipient who received an HBV-negative liver allograft. This virological condition is commonly considered at a very low risk of reactivation (<10%), and anti-HBV prophylaxis is not recommended. The mechanisms of HBVr in anti–HBc-positive patients remain debated with 2 possible explanations in LT recipients treated with DAA: (a) a very low inoculum associated with a prolonged incubation period after the DAA therapy, as recently proposed4; (b) immunosuppression due to the antirejection therapy and to the decrease of neutralizing antibodies (anti-HBs), as recently described.3 The clinical consequence could be on the one hand a lower risk of HBVr, minor clinical relevance (only HBsAg-reappearance) and early timing (on-therapy) with IFN, on the other hand, a higher risk of HBVr, greater clinical relevance (hepatitis flare) and late timing (off-therapy) with DAA. Therefore, considering the lack of similar reports of HBVr in large cohorts of anti–HBc-positive LT patients treated for HCV recurrence, clinicians should be aware of this rare phenomenon and evaluate patients with alanine aminotransferase flare for HBVr even in the long term after DAA treatment.